JULY
1961
SYSTHESIS O F PHENOLIC KETONES TTITI-I B O R O S TRIFLUORIDE
acetic acid a t pH 3-4 for approximately 1 day, and the solvent, was evaporated in a stream of nitrogen. The solid residue was redissolved in aqueous solution and stirred a t pH 6.4 for 3 hr. Evaporation of the water left a solid residue that gave a weakly positive Bratton-Marshall test. The solid was, therefore, redissolved in water, treated with activated carbon, and recrystallized from water. The colorless needles that separated gave ultraviolet and infrared spectra identical with those of Z,%diazahypozanthine dihydrate prepared from 5-amino-v-triazole-4-carboxamide without isolation of the diazo derivative. Spectroscopic determinations. Stock solutions of 5-diazo. imidazole-4-carboxamide for the ultraviolet studies were prepared by adding the solvent in the dark to a specimen weighed to the nearest microgram. Each stock solution was stored in the dark during the determination of stability a t a given pH. Initial concentrations of the diazoimidazole (11) were near 10 mg./l.
[CONTRIBUTION FROM THE
240 1
All ultraviolet spectra were recorded with a Beckman Model DK-2 spectrophotometer or with a Cary Model 14 spectrophotometer. The infrared spectra were determined in pressed potassium bromide disks with a Perkin-Elmer Model 21 spectrophotometer.
Acknowledgment. The authors are indebted to Mr. C. A. O’Dell for technical assistance; to Dr. W. J. Barrett, Dr. W. C. Coburn, Jr., and associates of the Analytical Section for spectral determinations; and to Mr. W. F. Fitagibbon and associates of the Organic Preparations Section for large quantities of starting materials. Microanalyses were performed by the Galbraith Microanalytical Laboratories, Knoxville, Tenn. BIRMINGHAM, ALA.
RADIUM INSTITUTE, UNIVERSITY
OF
PARIS]
Compounds with Potential Activity Against Lethal Radiations. VIII. Synthesis of Phenolic Ketones by Means of Boron Trifluoride iY. P.
BUU-HO’i A N D N. D. XUONG
Received September 1, 1960 Boron trifluoride in the presence of hydrogen fluoride proved an excellent catalyst for the synthesis of phenolic ketones, prepared for evaluation of their protective action against lethal radiations. The naphthols and pyrogallol gave monoketones, while hydroquinone was disubstituted. 4-.4cylcatechols were best prepared by acylation of guaiacol and subsequent demethylation.
In earlier papers,* we described how a number of phenolic ketones, especially those bearing a longchain acyl group, possess significant protective properties against whole-body x-ray irradiation in mice. Continuing this research, we have now synthesized phenolic ketones derived from diand triphenols and from CY- and @-naphthol. The most convenient method for these syntheses was the condensation of carboxylic acids with the phenols in presence of boron trifluoride mixed with some hydrogen fluoride (Le., the gas produced by the reaction of oleum on potassium fluorborate), the hydrogen fluoride enhancing the condensing qualities of boron trifluoride. In these conditions, a temperature of 70’ was sufficient to complete the condensation. The procedure is particularly useful for preparing ketones with long chains, as the Nencki, Friedel-Crafts, or Fries reactions customarily used may lead to splitting or rearrangement of such chains. Thus, with pyrogallol, arach-
(1) A. Lacassagne, J. F. Duplan, and N. P. Buu-HoY, J . .VulZ. Cancer Inst., 15, 915 (1955).
idic acid gave 4-arachidoylpyrogallol (I), and with a- and @naphthol, 2-arachidoyl-1-naphthol (11) and 1-arachidoyl-2-naphthol (111), all in excellent yields and without by-products. Similarly, 5-pentadecylresorcinol was easily converted with the appropriate acids, into 6-pentadecyl-4-resacetophenone (IV), 5-pentadecyl-4-respropiophenone
&OH I11
,I0 CO-R ToH
IV. R = CHI V. R = C2H5 -7. R = CH2-CeH5
(1’), and 5-pentadecyl-4-phenacetylresorcinol (VI), where in similar conditions the Xencki reaction gave but poor results.2 The acylation of catechol was far less easy to achieve (this lack of reactivity had already been noted in n’encki reactions3), and 4-acylcat,echols were more readily accessible by boron trifluoridecatalyzed acylation of guaiacol and demethylation of the resulting 2-methoxy-4-acylphenols by means ( 2 ) Cf. R. D. Haworth and D. Woodcock, J . Chem. Soc.. 999 (1946). (3) ?;. P. Buu-HoY, J . Org. Chcm., 19, 1770 (1954).
BVU-HOT
2302
VII. R -= CH3 VIII. R = CJHS
IX
of pyridine hydr~chloride.~4-Propionylcatechol and 4-butyrylcatechol were thus obtained in good yields via 2-met hoxy-4-propionylphenol (VII) and 2-methoxy-4-butyrylphenol (T'III) respectively. This method also provides a convenient route to the 3-ethers of acylcatechols which otherwise are not easily accessib1e.j Whereas in all the above instances only monoacylation was observed. in the case of hydroquinone ptopionylation gave 2,5-dipropionylhydroquinone (IX). In biological tests of these ketones for their protective action against the lethal effects of wholebody x-ray irradiation in mice, 4-arachidoylpyrogallol, 2-arachidoyl-1-naphthol) and l-arachidoyl-2-naphthol shon-ed significant activity. EXPERIMESTAL
i - ~ ~ r u c h i d o u l p y r o g a l l o(I). l The catalytic mixture of boron trifluoride and hydrogen chloride was produced by t,he reartion of oleum on potasfium fiuoroborate in a proportion of 8 1. of oleum to 7 kg. fluorborate; a mixture of 48 g. of arachidic acid, 30 g. of pyrogallol, and 30 ml. of anhydrous xylene TTas saturated, during 20 min., with the gas thus generated, and during the last 5 niin. the flask was heated on a v-ater bath at, 70" t o complete the condensation. After cooling, the product TT-astreated Kith water and xylene was added; the xylene layer Tyas washed first with aqueous sodium carbonate, then n-ith water, and dried over sodium sulfate, and the solvent evaporated in oucuo. The solid rrmaining was recrystallized first from cyclohexane, then from acetone, giving fine colorless needles, m.p. 99". Yield: 9OCE. The product was readily soliible in lipids and showed pronoiincecl antioxidant activity (substrate, linseed oil). Its solution in ethanol gave a bright yellow coloration rvith sodium hydroxide. Calcd. for c, 74.3; H, 10.6. Found: C, 74.3; H, 10.7. ~ - ; ~ r a c i i i d o g l - l - n n p ~ ~(IT). f h o ~h mixture of 10 g. of anaphthol, 15 g. of arachidic acid, and 15 ml. of anhydrous xylene n-as treated with boron trifluoride-hydrogen fluoride and the product worked up as above. After t w o recrgstallizations from cyclohexane, the ketone was obtained in 707, yield as shiny pale j,ellow needles, m.p. 93", very soluble in lipids a i d giving a y e l l o ~coloration in a solution of sodium hydroxide in ethmol. .Inal. Calcd. for C a O H 4 6 0C? ~ :81.:3; H, 10.6. Found: C, 81.6; H, 10.4. l-"-lrachido?/l-~-naphthoE (111). Prepared in 80rc yield from 10 g. of p-naphthol and 15 g. of arachidic acid in 15 nil. of xylene, this ketone crystallized from cycloliexane in shiny rellowish needles, m.p. 76", wit'h properties similar to its isomer. 14)
C'f. 1.P. BLIU-HOT, Rec. trav. chiirz., 68, 759 (1949).
( 5 ) T. Rrichstein, Helw. chznz. Acta, 10, 394 (1927).
~ 0 1 , .2 6
ASD XUOSG
Anal. Calcd. for C3&02: c, 81.3; H, 10.6. Found: (J, 81.5; H, 10.5. j-Peritadecyl-4-resacetophenone (11;). The 5-pentacldc)-lresorcinol6 used in this work (m.p. 95') was prepared b y catalytic hydrogenation of cardol. A mixture of 20 g. of this phenol, 30 nil. of xylene, and 30 ml. of acetic acid was saturated with t'he catalyst for 1 hr. a t 50-60", and the reaction product left t o stand overnight. After decomposition with ice and neutralization with sodium carbonate, the solid obtained was recrystallized twice from ethanol, giving fine colorless needles, m.p. 63". Yield: 75%. Anal. Calcd. for C?3H3&: C, 76.2; H, 10.6. Found: C, 76.0; H,10.8. 5-Pentadecyl-4-respropiophenone (V). Prepared as above, and in similar yield, from propionic acid, this ketone crystallized from ethanol in fine colorless prisms, m.p. 76". Anal. Calcd. for C?dH4003: C, 76.6; H, 10.7. Found: C, 76.4; H, 10.5. 5--PentadecyZ-4-phenacet~iresorcinoZ(VI). Prepared with a excess of phenylacetic acid, the product of the condenn Tyas purified by treatment m-ith a hot aqueous solution of sodium carbonate. Crystallization from ethanol gave yellowish needles, m.p. 105". I n this as in the t ~ v oprevious cases, the Sencki reaction (heating of 5-pentadecylresorcinol xvith the corresponding acid in presence of anhydroiis zinc chloride) furnished several unidentified by-products. Anal. Calcd. for C?s&O3: C, 70.4: II, 9.6. Found: C, 79.1; H, 9.8. Preparation of 4-propionylcaleciiol. A mixture of 20 g. of freshly redistilled guaiacol, 15 g. of glacial acetic acid, and 30 nil. of xylene Tvas saturated with t'he catalyst a t 60-70", and the product kept overnight a t room temperatiire. After the usiial treatment, and vacuum-distillation of the reaction product, 2-mefhor~-4-propionylphe~one(VII) \vas obtained in almost theoretica: yield as a pale yellow oil, b.p. 182"/12 mm., which readily solidified; recrystallization from hexane gave shiny colorless leaflets, m.p. 54". Anal. Calcd. for CLoHI2O3: C, 66.7; E,6.7. Found: C, 66.5; H, 6.7. X mixture of 5 E. of the foregoinn ketone and 10 g. of redistilled pyridine- hydrochloridue was gently refluxed for 10 min.; after cooling and addition of dilute hydrochloric acid? the precipit,ate formed was washed with 11-ater, and recrystallized from aqueous ethanol, giving 4-propionylcatechol in 807, yield, as shiny colorless prisms, m.p. 142." Prepnrafion qf 4-butyrylcatechol. R M e l h o z y - ~ - b u t y r y l p h e n o l (TIII), prepared from guaiacol and butyric acid as for tjhe l o m r homolog, was purified by vacuum distillation: the pale yellow oil obtained, b.p. 202"/12 mm., readily solidified in hexane, to give fine colorless prisms, m.p. 45". Anal. Calcd. for CI~H&: C, 68.0: H, 7.3. Found: C, 67.7; €I, 7.5. Demethylation of 5 g. of this ketone with 10 g. of pyridine hydrochloride afforded 4-bz~~yr$catechol,crystallizing from aqueous ebhanol in fine colorless prisms m.p. 149'. d,j-D~~ropionvlh~drcqirinone (IX). The condensation of hydroquinone with propionic acid in xylene was difficult to achieve and necessitated heating on a boiling water bath. Repeated crystallization of the reaction product from aqueous methanol afforded a 7t7, yield of this diketone a3 large yelloxish prisms. m.p. 1.51-152". This compound n-as sul~limahleand gave a yellow solution in sulEuric acid. .Inol. Cnlcd. for C;213,,04:C,64.8;H, 6.3; 0, 28.8. Found: C, 64.5; H. 6.0; 0,29.0. PARIS
v>F H A X C E
(6) For further deriyatives of this diphenol, see R . N. Chakravarti and S . P. BLIU-HOT,Bull. Soc. chzm. F i a n c e , 1498 (1959).
